Transformation of human colonic epithelial cells confers on them sensitivity to new mitogenic signals. Fecal diglycerides (DGs), composed of oleic, myristic, or palmitic acid residues, were found in vivo at uM to mM concentrations (Cancer Res.49 :544-548, 1989), and were probably derived from dietary fat. When DGs were added to colon cells in vitro in detergent-micelles at physiological concentrations, they induced proliferation of premalignant colonocytes, some carcinoma cells, but not normal colonocytes (ibid). DGs also increased urokinase secretion from carcinoma cells. Parallel to this selective biological activity on tumor cells, fecal diglycerides induced the phosphorylation on tyrosine residues of a 63 kd membrane protein in carcinoma and adenoma cells but not normal cells, as shown by immunoblotting with antiphosphotyrosine monoclonal antibody. We propose to continue to study the mechanism of signal transduction initiated by DGs in colon cells through the tyrosine kinase substrate pp63.